The aim of this subproject is to test the viral vectors developed in the Program Project in physiological significant conditions relevant to cardiovascular disease. Since many aspects of cardiovascular disease involve overexpression of genes of the renin-angiotensin system, this project will use a "reduction of function" approach by delivering antisense to angiotensin converting enzyme (ACE) mRNA delivered by viral vectors. We hypothesize that antisense to ACE will reduce overexpression of systemic an dlocal tissue renin-angiotensin systems. We will begin with 3 viral vectors, the adeno,m adeno-associated and retrovirus vectors. Using the most advanced improvements in these vectors from other subprojects in this proposal. We will stydy the delivery of ACE-AS 1). To characterize the delivery system in cells inclduign pig endothelium, neurons, astroglia and vascular smooth muscle on infection efficiency, toxicity and reduction of ACE activity, 2) To test the effectiveness of ACE-AS delivery in vivo and observe the fate of vectors, the pathological responses, the duration of effectiveness and the change in plasma ACE, Ang II and Ang I, 3) To deliver ACE-AS directly into tissues, including brain, heart and arteries and measure the effects of local ACE activity 4) To test the ACE-AS vectors in rat models of renovascular hypertension, pulmonary hypertension, genetic hypertension and artery restenosis and their effectiveness on reducing blood pressure and vascular regrowth. These experiments willprovide information on the delivery system that could be successful in gene therapy for cardiovascular disease models.